Analysis of the spontaneously-occurring, X-linked recessive mutation scurfy (sf) indicates that further study of these mice may reveal molecular events important for the regulation of T cell activation. Evidence to date suggests that the sf disease is mediated by CD4 T cells which are hyperresponsive to activation through their antigen receptor, yielding unchecked T cell proliferation and cytokine secretion and premature death. Two distinct hypotheses could explain the sf phenotype. The sf gene product could function in a signaling cascade activated by TCR ligation or could act in a regulatory pathway of T cell activation. The aims are to: 1) Ascertain whether the sf phenotype is the result of dysregulated TCR signaling. The activity of T cell-specific transcription factors will be evaluated in sf and normal T cells. Also, the involvement of the sf mutation in more TCR proximal signaling events will be examined using both biochemical and genetic approaches. 2) Determine whether the sf mutation is a defect in the CD28/CTLA-4:B7-1/B7-2 pathways that modulate T cell activation. The contribution of the CD28 costimulatory pathway to the sf phenotype will be examined in CD28-/-/sf mice. Biochemical analyses will be utilized to assess the role of the CTLA-4 signaling in the sf phenotype.